SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS PEDIAZOLE (erythromycin and sulfisoxazole) , SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKINRASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders. (See

There have been reports of hepatic dysfunction with or without jaundice, occurring in patients receiving oral erythromycin products.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Pediazole (erythromycin and sulfisoxazole) , and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

After diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration to prevent congenitalsyphilis. Infants born to women treated during pregnancy with erythromycin for early syphilis should be treated with an appropriate penicillinregimen.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels. (See package insert for lovastatin.)

PRECAUTIONS

General: Erythromycin is principally excreted by the liver. Caution should be exercised when erythromycin is administered to patients with impaired hepatic function. (See CLINICAL PHARMACOLOGY and WARNING sections.)

Prolonged or repeated use of erythromycin may result in an overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, erythromycin should be discontinued and appropriate therapy instituted.

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.

Sulfonamides should be given with caution to patients with impaired renal or hepatic function and to those with severe allergy or bronchial asthma. In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur; this reaction is frequently dose-related.

Information for Patients: Patients should maintain an adequate fluid intake to prevent crystalluria and stone formation.

Laboratory Tests: Complete blood counts should be done frequently in patients receiving sulfonamides. If a significant reduction in the count of any formed blood element is noted, Pediazole (erythromycin and sulfisoxazole) should be discontinued. Urinalysis with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. Blood levels should be measured in patients receiving a sulfonamide for serious infections. (See INDICATIONS AND USAGE.)

Drug Interactions: Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy.

Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels.

There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to this drug may be more pronounced in the elderly.

Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acuteergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

Erythromycin has been reported to decrease the clearance of triazolam and midazolam and thus may increase the pharmacologic effect of these benzodiazepines.

The use of erythromycin in patients concurrently taking drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these other drugs. There have been reports of interactions of erythromycin with carbamazepine, cyclosporine, hexobarbital, phenytoin, alfentanil, diisopyramide, lovastatin, and bromocriptine. Serum concentrations of drugs metabolized by the cytochrome P450 system should be monitored closely in patients concurrently receiving erythromycin.

It has been reported that sulfisoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Pediazole (erythromycin and sulfisoxazole) is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

It has been proposed that sulfisoxazole competes with thiopental for plasma protein binding. In one study involving 48 patients, intravenous sulfisoxazole resulted in a decrease in the amount of thiopental required for anesthesia and in a shortening of the awakening time. It is not known whether chronic oral doses of sulfisoxazole have a similar effect. Until more is known about this interaction, physicians should be aware that patients receiving sulfisoxazole might require less thiopental for anesthesia.

Carcinogenesis: Pediazole (erythromycin and sulfisoxazole) has not undergone adequate trials relating to carcinogenicity; each component, however, has been evaluated separately. Long-term (21 month) oral studies conducted in rats with erythromycin ethylsuccinate did not provide evidence of tumorigenicity. Sulfisoxazole was not carcinogenic in either sex when administered to mice by gavage for 103 weeks at dosages up to approximately 18 times the recommended human dose or to rats at 4 times the human dose. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides, and long-term administration of sulfonamides has resulted in thyroid malignancies in this species.

Mutagenesis: There are no studies available that adequately evaluate the mutagenic potential of Pediazole (erythromycin and sulfisoxazole) or either of its components. However, sulfisoxazole was not observed to be mutagenic in E. coli Sd-4-73 when tested in the absence of a metabolic activating system. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25% of diet.

Impairment of Fertility: Pediazole (erythromycin and sulfisoxazole) has not undergone adequate trials relating to impairment of fertility. In a reproduction study in rats given 7 times the human dose per day of sulfisoxazole, no effects were observed regarding mating behavior, conception rate or fertility index (percent pregnant).

Pregnancy: Teratogenic Effects. Pregnancy Category C. At dosages 7 times the human daily dose, sulfisoxazole was not teratogenic in either rats or rabbits. However, in two other teratogenicity studies, cleft palates developed in both rats and mice after administration of 5 to 9 times the human therapeutic dose of sulfisoxazole.

There is no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25% of diet) prior to and during mating, during gestation, and through weaning of two successive litters. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Erythromycin has been reported to cross the placental barrier in humans, but fetal plasma levels are generally low.

There are no adequate or well-controlled studies of Pediazole (erythromycin and sulfisoxazole) in either laboratory animals or in pregnant women. It is not known whether Pediazole (erythromycin and sulfisoxazole) can cause fetal harm when administered to a pregnant woman prior to term or can affect reproduction capacity. Pediazole (erythromycin and sulfisoxazole) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Kernicterus may occur in the newborn as a result of treatment of a pregnant woman at term with sulfonamides. (See CONTRAINDICATIONS.)

Labor and Delivery: The effects of erythromycin and sulfisoxazole on labor and delivery are unknown.

Nursing Mothers: Both erythromycin and sulfisoxazole are excreted in human milk. Because of the potential for the development of kernicterus in neonates due to the displacement of bilirubin from plasma proteins by sulfisoxazole, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. (See CONTRAINDICATIONS .)